Traditionally, immune therapeutic vaccination against viruses has utilized either live attenuated preparations, whole killed virus or recombinant proteins. Of these approaches, only live attenuated virus preparations activate all arms if the immune system in a manner similar to infection. Genetic immunization is dependent upon injection of a nucleic acid, sequence directly into a host target tissue. In theory, direct genetic immunization would mimic aspects of attenuated vaccines in that synthesis of specific foreign proteins would be accomplished in the host and become the subject of immune surveillance via both the MHC class I and class II pathways. The use of this new technology to immunize animals with human immunodeficiency virus type 1 (HIV-1) envelope gp160 DNA constructs and achieve relevant immune responses has been reported by this group. Antisera from genetically immunized animals including, mice, rabbits and non-human primates, contains anti-HIV envelope glycoprotein immune responses. The antiserum neutralizes HIV-1 infection and inhibits cell to cell infection in vitro. This technology induced both T cell proliferation and isotype switching consistent with the production of relevant T helper immune responses. Lysis of relevant env expressing targets was induced by immune spleenocytes from mice and primates. Through the development of an in vivo murine model it was demonstrated that mice can reject lethal cell challenge through specific immune responses directed at HIV proteins. This in vivo anti HOV data suggest the utility of this technology for anti-HIV immmune therapeutic strategies. This grant proposal will focus on the safety of this strategy and its ability to effectively induce immune responses in humans and non-human primates previously infected with HIV or SIV. Project 1 will evaluate the safety, immunogenicity and efficacy of simian immunodeficiency virus (SIV) constructs encoding gag/pol or env given singly or in combination to rhesus macques infected with SIV. Project 2 will evaluate the safety, immunogenicity and efficacy of genetic immunization with human immunodeficiency virus (HIV) constructs encoding gag/pol or env given singly or in combination to chimpanzees infected with HIV. Project 3 will evaluate the safety, immunogenicity and responses to genetic immunization with HIV constructs encoding gag/pol or env given singly or in combination in HIV+humans. A molecular core will be responsible for development of clinical grade material for genetic immunization. An administrative core will coordinate the interactions and sample handling. These studies will generate critical data regarding athe safety, immunogenicity and utility of genetic inoculation with HIV-1 genes to induce immune responses as potential immune therapy for HIV-1.